DESCRIPTION: Applicant's Abstract The overall objective of our research over the past four years has been to determine, in vivo, the cellular neurophysiological events underlying heroin self-administration and other reinforced behaviors. Toward this aim our proposed experiments have focused on the rat nucleus accumbens (NAcc) of the basal forebrain, its most proximal connections and transmitter candidates. In the past funding period we have determined that NAcc neurons are selectively responsive to novel external stimuli by exhibiting inhibition of their discharge rate and similarly decrease their discharge rate during discrete episodes of heroin self- administration. However, we have been struck by the relatively small number of accumbens neurons (less than 25% of all recorded cells) that exhibit these correlations either during sustained heroin self- administration of focused attention. These observations have suggested to us that overall role of these neurons in drug self-administration remains an open question. However, recent studies conducted in our laboratory indicate that other sites in the mesocorticolimbic system respond to self-administered heroin with greater sensitivity and with differential patterns of responsiveness depending on exposure history. We hypothesize that a cell population of the ventra tegmental region of the brain stem, particularly the incompletely characterized GABA containing non-DA projection neurons, are a significant new cellular substrate potentially integrating the perception of rewarding stimuli and pre-motor integrative events. Studies designed in this renewal will focus on this new cellular substrate and evaluate its comparative role and hierarchy in drug-related reward circuits. Techniques of both extracellular and intracellular recording in conjunction with immunohistochemical techniques taken to the EM level will be used to assess both the physiological response of these neurons to heroin administration as well as to evaluate their efferent projections and transmitter related receptors. Self-administration studies will focus on the side-by-side comparison of cellular activity in the NAcc and the ventral tegmental GABA neurons during acquisition and maintenance of heron self administration. These multidisciplinary studies are directed at discovering the initial, sequential, and potentially plastic alterations in cellular responses in brain circuits critical for drug self - administration. Data obtained from these extended studies will potentially provide new insights into the cellular syntax of reinforcement circuits relevant for understanding drug abuse.